P-gp (P-glycoprotein) is a membrane transporter belonging to the ABC (ATP Binding Cassette) family and is expressed in several organs such as kidney, liver, lung, intestine and central nervous system (CNS). This protein is involved in active transport of xenobiotics and therefore plays a key role in absorption and detoxification processes. P-gp is encoded by MDR1 and MDR2 genes in humans.
Recently, a correlation between the alteration of P-gp activity and/or expression in the CNS and the onset of neurodegenerative diseases such as Parkinson's and Alzheimer's has been demonstrated (Vogelgesang, S. et al. 2002, Pharmacogenetics, 12, 535-541; Rapposelli et al., 2009, Curr. Top. Med. Chem., 9, 209-217).
In particular, Alzheimer's disease is characterized by the presence of plaques of insoluble β-amyloid (Aβ) and neurofibrillary tangles. Recently, in the brain of AD patients an inverse correlation between Aβ accumulation in CNS and P-gp activity has been detected (Kuhnke, D. et al., 2007, Brain pathol., 17, 347-353). This finding led to assign to P-gp a critical role in Aβ efflux from the brain.
Therefore, P-gp is important not only as a target for the prevention and treatment of the neurodegenerative disorders, but also for the development of radiotracers for use in imaging method such as PET and SPECT analyses to detect the activity of this protein, and therefore the onset of neurodegenerative disease.
In the last years, some radiotracers were developed, even if their diagnostic use was limited by their low basal uptake, the production of radio metabolites falsifying the analysis and their poor selectivity towards other ABC transporters.
P-gp substrates such as [11C] verapamil, [11C] loperamide and [11C]N-desmethyl-loperamide were used to visualize the activity of P-gp, but they showed a low basal uptake at the blood brain barrier (BBB) and the production of radio metabolites alternating the analysis. (Bart, J. et al., 2003, Neuroimage, 20, 1775-1782, Liow, J. S. et al., 2009, J. Med. Chem., 49, 1328-1335).
P-gp inhibitors such as [11C] elacridar, [11C] laniquidar and [11C] tariquidar were tested for the detection of P-gp expression. (Dörner, B. et al. 2009, J. Med. Chem, 52, 6073-6082, Luurtsema, G. et al., 2009, Nucl. Med. Biol., 36, 6073-6082; Bankstahl, J. P. et al., 2008, J. Nucl. Med. Chem., 49, 1328-1335) but the absence of selectivity towards other ABC transporters, such as BCRP, the low brain uptake and a different dose-dependent behavior has limited their diagnostic use.
In Kannan et al. (Kannan, P. et al., 2009, Clin. Pharmacol. Ther., 86, 368-377 and Kannan, P. et al., 2010, ACS Chem. Neurosci) the pharmacokinetic and pharmacodynamic limits in the development of P-gp PET tracer are shown.
Other compounds for use in the in vivo diagnosis of Alzheimer disease are shown in the following international patent WO0071101.
Scope of the present invention is to provide novel compounds for use as radiotracers in vivo diagnosis of neurodegenerative diseases involving P-glycoprotein activity without the disadvantages of prior art's compounds.